1. Field of the Invention
The present invention relates to the oral delivery of polar bioactive agents particularly polypeptides which by this route are slowly absorbed and more especially to the enhancement of this delivery by formulations which contain a hydroxyaromatic acid.
As employed in this application, the term "polar bioactive agents" refers to those therapeutic substances which, due to their polar nature, are slowly absorbed from the gastrointestinal tract and include particularly, polypeptides which have three or more residues of amino acids with a molecular weight of 4000 or less.
2. Description of the Prior Art
It is well known to the art that a number of bioactive agents are so polar that they are only slowly absorbed from the gastrointestinal tract. Consequently, these agents, on the basis of the current art, must be administered by the intravenous or intramuscular route or in excessively large oral doses in order to attain clinical efficacy. Similarly, there are a number of other polar bioactive agents such as the polypeptides which, due to their hydrophilic nature, are also slowly absorbed from the gastrointestinal tract. The hydrophilic, polar nature of these agents precludes their rapid absorption so that even the small percentage which is absorbed is subject to a long residency time in the gastrointestinal environment where both acidic and enzymatic degradation contribute to their poor bioavailability. It is therefore clear that any factor which enhances the rate of absorption will demonstrate improved clinical efficacy.
Many attempts have been made to improve the oral absorption of these polar bioactive agents. The degradation caused by the gastric acid and enzymes can be partially overcome by coating. This process in some instances can lead to some enhanced oral absorption, but in no case does it allow complete absorption. Other approaches center on the reduction of the hydrophilicity by preparing a chemical derivative which is more lipophilic. The more lipophilic derivative is more rapidly absorbed so that the residency time in the degrading gastric medium is minimized.
In spite of the numerous attempts to prepare a dosage form of these polar bioactive agents, there still exists a clear and present need for a novel method to enhance the oral absorption of polar bioactive agents, particularly polypeptides. Said method would permit the oral use of a number of polypeptides, and would provide an improved oral dosage form for such polypeptides.